首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   539篇
  免费   39篇
  国内免费   27篇
耳鼻咽喉   1篇
儿科学   3篇
妇产科学   7篇
基础医学   166篇
口腔科学   32篇
临床医学   16篇
内科学   51篇
皮肤病学   14篇
神经病学   107篇
特种医学   18篇
外科学   65篇
综合类   39篇
预防医学   4篇
眼科学   19篇
药学   25篇
中国医学   8篇
肿瘤学   30篇
  2023年   3篇
  2022年   3篇
  2021年   9篇
  2020年   10篇
  2019年   4篇
  2018年   6篇
  2017年   9篇
  2016年   15篇
  2015年   19篇
  2014年   21篇
  2013年   43篇
  2012年   28篇
  2011年   30篇
  2010年   28篇
  2009年   20篇
  2008年   31篇
  2007年   26篇
  2006年   38篇
  2005年   20篇
  2004年   20篇
  2003年   21篇
  2002年   20篇
  2001年   19篇
  2000年   5篇
  1999年   14篇
  1998年   11篇
  1997年   16篇
  1996年   13篇
  1995年   18篇
  1994年   19篇
  1993年   13篇
  1992年   13篇
  1991年   10篇
  1990年   6篇
  1989年   4篇
  1988年   5篇
  1987年   2篇
  1986年   3篇
  1985年   2篇
  1984年   3篇
  1982年   1篇
  1981年   2篇
  1980年   1篇
  1978年   1篇
排序方式: 共有605条查询结果,搜索用时 15 毫秒
1.
Background: Microfracture is a common procedure for cartilage repair, but it often produces inferior fibrocartilage. We previously reported that a super positively charged SOX9 (scSOX9) promoted hyaline-like cartilage regeneration by inducing bone marrow derived mesenchymal stem cell differentiation into chondrocytes in vivo. Here we examined the long-term efficacy of cartilage repair induced by microfracture with scSOX9 by assessing the biomechanical property of the repaired cartilage.Methods: A cartilage defect was created at the right femoral trochlear groove in New Zealand female rabbits and microfracture was performed. The scSOX9 protein was administered at the site of microfracture incorporated in a collagen membrane.Results: At 12 and 24 weeks, scSOX9 treatment induced hyaline-like cartilage while collagen-membrane alone induced fibrocartilage and mutant scSOX9-A76E poorly induced cartilage repair. The cartilage matrix in scSOX9-treated group showed highly enriched proteoglycan content. Consistent with the histological feature and the thickness of the repaired cartilage, the mechanical property of scSOX9-induced cartilage was also similar to that of normal cartilage.Conclusion: This long-term in vivo study demonstrated that in combination with microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage which was durable in long-term. This technology has the potential to translate into clinical use for cartilage repair to prevent progression to osteoarthritis.  相似文献   
2.
Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio‐exome sequencing identified novel biallelic CSGALNACT1 variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1 encodes CSGalNAcT‐1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT‐1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients’ fibroblasts compared to controls. Our data indicate that biallelic loss‐of‐function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1‐CDG.  相似文献   
3.
Abstract

Increasing evidence points to extracellular matrix (ECM) components playing integral roles in regulating the muscle satellite cell (SC) niche. Even small alterations to the niche ECM can have profound effects on SC localization, activation, self-renewal, proliferation and differentiation. This review will focus on the ECM components that comprise the niche, how they are modulated in health and disease and how these changes are thought to affect SC function. Particular emphasis will be placed on the pathological niche and interventions that aim to restore healthy structure and function, as a better understanding of the interplay between the SC and its environment will drive more targeted and effective therapies.  相似文献   
4.
5.
6.

Background

VAR2CSA is a large polymorphic Plasmodium falciparum protein expressed on infected erythrocytes (IE) that allows their binding in the placenta, thus precipitating placental malaria (PM). The N-terminal part of VAR2CSA that contains the binding site to placental chondroitin sulfate A (CSA) is currently recognized as the most attractive region for vaccine development. An ultimate challenge is to define epitopes in this region that induce a broad cross-reactive adhesion inhibitory antibody response.

Methods

Based on phylogenetic data that identified a dimorphic sequence motif in the VAR2CSA DBL2X, we raised antibodies against the NTS-DBL2X constructs containing one sequence or the other (3D7 and FCR3) and tested their functional properties on P. falciparum isolates from pregnant women and on laboratory-adapted strains.

Results

The CSA binding inhibitory capacity of the antibodies induced varied from one parasite isolate to another (range, 10%–100%), but the combined analysis of individual activity highlighted a broader functionality that increased the total number of isolates inhibited. Interestingly, the differential inhibitory effect of the antibodies observed on field isolates resulted in significant inhibition of all field isolates tested, suggesting that optimal inhibitory spectrum on field isolates from pregnant women might be achieved with antibodies targeting limited variants of the N-terminal VAR2CSA.

Conclusions

Our findings indicate that the NTS-DBL2X region of VAR2CSA can elicit strain-transcending anti-adhesion antibodies and suggest that the combination of the two major variants used here could represent the basis for an effective bivalent VAR2CSA-based vaccine.  相似文献   
7.
Non‐specific cytotoxins, including paclitaxel and sirolimus analogues, currently utilized as anti‐restenotic therapeutics, affect not only smooth muscle cells (SMCs) but also neighbouring vascular endothelial cells (ECs). These drugs inhibit the formation of an intact endothelium following vessel injury, thus emphasizing the critical need for new candidate therapeutics. Utilizing our in vitro models, including EC monolayers and both hyperplastic and quiescent EC–SMC co‐cultures, we investigated the ability of DS–SILY20, a decorin mimic, to promote EC health. DS–SILY20 increased EC proliferation and migration by 1.5‐ and 2‐fold, respectively, which corresponded to increased phosphorylation of ERK‐1/2. Interestingly, IL‐6 secretion and the production of both E‐selectin and P‐selectin were reduced in the presence of 10 μm DS–SILY20, even in the presence of the potent pro‐inflammatory cytokine platelet‐derived growth factor (PDGF). In hyperplastic and quiescent EC–SMC co‐cultures, DS–SILY20 treatment reduced the secretion of IFNγ, IL‐1β, IL‐6 and TNFα, corresponding to a 23% decrease in p38 phosphorylation. E‐selectin and P‐selectin expression was further reduced following DS–SILY20 treatment in both co‐culture models. These results indicate that DS–SILY20 promotes EC health and that this decorin mimic could serve as a potential therapeutic to promote vessel healing following percutaneous coronary intervention (PCI). Copyright © 2015 John Wiley & Sons, Ltd.  相似文献   
8.
A cell culture system is described in which purified mononuclear phagocytes may be cultured with a cartilage substrate which is radiolabelled in its proteoglycan. Resident mouse peritoneal macrophages degraded this substrate, and did so more avidly if cultured in direct contact with it. There was no evidence for complete intralysosomal degradation of the proteoglycan of the cartilage. Lysates were found to contain considerable activity at pH 7, which was inhibited by the presence of 10% serum, or by boiling the lysate.

Proximity of macrophages to the substrate did not induce selective release of the lysosomal marker enzyme hexosaminidase, and concentrated enzymes secreted from the macrophages after treatment with the lysosomotropic agent ammonium chloride were ineffective in degrading cartilage at neutral pH.

The active enzyme in macrophage lysates at neutral pH was found to be sedimentable by 100,000 × g centrifugation for 1 hour, in absence of lysosomal protective agents. There is evidence for a cell membrane-associated process in the degradation of cartilage by these cells, which may be a proteolytic, endoglycosidic or free radical-mediated event.  相似文献   
9.
The turnover of proteoglycans in bovine articular cartilage was determined in explant cultures, maintained at 32°C or 37°C. Both the rate of proteoglycan synthesis and the release of newly synthesized proteoglycans were decreased in cultures incubated at 32°C compared to 37°C.

At both temperatures the newly synthesized proteoglycans were similar in hydrodynamic size and chain length of the glycosaminoglycans. However, the ratio of 6-sulfated disaccharides over 4-sulfated disaccharides of the newly synthesized glycosaminoglycans, differed less from the endogenous ratio at 32°C than at 37°C.

At both temperatures, the incorporated 35S-sulfate is released from explants in two pools. Twenty-three percent of the 35S-radiolabel was released into the culture medium during an initial short phase (t1/2 = 1.1 day at 32°C, 1.3 day at 37°C), 77% had a much longer half-life. The lowered temperature markedly decreased the release of 35S-sulfate with a slow turnover (t1/2 = 60 days at 32°C, 38 days at 37°C).  相似文献   
10.
Soluble substances in the bovine nuchal ligament were removed by preliminary extractions with a buffer and dilute alkali solution. The insoluble residue was then extracted with 6 M guanidine HCl and with 6 M guanidine HCl containing a reducing agent (20 mM dithiothreitol) successively. Each of the two extracts contained a glycoprotein; that in the first extract was designated Glycoprotein A and that in the second Glycoprotein B. They were purified by ion-exchange chromatography and gel filtration till essentially homogeneous. Both proteins had similar molecular weights of 35,000 in SDS-polyacrylamide gel electrophoresis and by gel filtration, and their chemical compositions resembled each other closely. It is suggested that Glycoprotein B was present in the native state as a disulfide-bonded, aggregated form of Glycoprotein A. The compounds also showed similarity with the microfibrillar glycoprotein(s) previously reported in bovine nuchal ligament extracts.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号